product monograph diazepam - aa pharma
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PRODUCT MONOGRAPH
DIAZEPAM
Diazepam Tablets, USP
2 mg, 5 mg and 10 mg
Anxiolytics: Benzodiazepine derivatives
AA PHARMA INC. DATE OF REVISION:
1165 Creditstone January 07, 2019
Road, Unit#1
Vaughan, Ontario
L4K 4N7
Control #: 222573
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Table of Contents
PART I: HEALTH PROFESSIONAL INFORMATION .......................................................................................... 3 SUMMARY PRODUCT INFORMATION .................................................................................................................... 3 INDICATIONS AND CLINICAL USE .......................................................................................................................... 3 WARNINGS AND PRECAUTIONS .............................................................................................................................. 4 ADVERSE REACTIONS ............................................................................................................................................... 8 DRUG INTERACTIONS ................................................................................................................................................ 9 DOSAGE AND ADMINISTRATION ...........................................................................................................................14 OVERDOSAGE .............................................................................................................................................................15 ACTION AND CLINICAL PHARMACOLOGY .........................................................................................................16 STORAGE AND STABILITY .......................................................................................................................................17 SPECIAL HANDLING INSTRUCTIONS ....................................................................................................................17 DOSAGE FORMS, COMPOSITION AND PACKAGING ..........................................................................................18
PART II: SCIENTIFIC INFORMATION .................................................................................................................19 PHARMACEUTICAL INFORMATION .......................................................................................................................19 DETAILED PHARMACOLOGY ..................................................................................................................................20
TOXICOLOGY ..............................................................................................................................................................20 REFERENCES ...............................................................................................................................................................21
PART III: CONSUMER INFORMATION................................................................................................................22
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DIAZEPAM
Diazepam Tablets, USP
2 mg, 5 mg and 10 mg
PART I: HEALTH PROFESSIONAL INFORMATION
SUMMARY PRODUCT INFORMATION
Route of Administration Dosage Form / Strength All Non-medicinal Ingredients
Oral Tablet, 2 mg, 5 mg and 10
mg
D&C yellow #10 (5 mg only), FD&C blue
#1 (10 mg only), FD&C blue #2 (10 mg
only), FD&C yellow #6 (5 mg only),
lactose monohydrate, magnesium stearate,
microcrystalline cellulose and starch.
INDICATIONS AND CLINICAL USE
DIAZEPAM (diazepam) is useful in the symptomatic management of mild to moderate degrees of anxiety
in conditions dominated by tension, excitation, agitation, fear or aggressiveness, such as may occur in:
psychoneurosis, anxiety reactions due to stress conditions and anxiety states with somatic expression.
In acute alcoholic withdrawal, DIAZEPAM may be useful in the symptomatic relief of acute agitation,
tremor and impending acute delirium tremens.
DIAZEPAM is a useful adjunct for the relief of skeletal muscle spasm due to reflex spasm to local
pathology, such as inflammation of the muscle and joints or secondary to trauma; spasticity caused by
upper motor neuron disorders, such as cerebral palsy and paraplegia; athetosis and the rare "stiff man
syndrome".
Geriatrics
Elderly and debilitated patients are especially susceptible to dose-related adverse events and a reduced dose
is recommended (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics and DOSAGE
AND ADMINISTRATION, Dosing Considerations).
Pediatrics
DIAZEPAM is contraindicated in children under 6 months (see CONTRAINDICATIONS and DOSAGE
AND ADMINISTRATION, Children).
CONTRAINDICATIONS
Patients who are hypersensitive to other benzodiazepines, this drug or to any ingredient in the
formulation or component of the container. For a complete listing, see the Dosage Forms,
Composition and Packaging section of the product monograph.
Severe respiratory insufficiency.
Severe hepatic impairment (see WARNINGS AND PRECAUTIONS, Hepatic).
Sleep apnea syndrome.
Myasthenia gravis.
Narrow angle glaucoma.
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Children under six months of age due to lack of sufficient clinical experience.
WARNINGS AND PRECAUTIONS
Serious Warnings and Precautions:
RISKS FROM CONCOMITANT USE WITH OPIOIDS
Concomitant use of DIAZEPAM and opioids may result in profound sedation, respiratory
depression, coma and death (see WARNINGS AND PRECAUTIONS, General, Concomitant
use with opioids).
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment
options are inadequate.
Limit dosages and durations to the minimum required.
Follow patients for signs and symptoms of respiratory depression and sedation.
General
Benzodiazepines are only indicated when the disorder is severe, disabling or subjecting the individual to
extreme distress.
Benzodiazepines are not recommended for the primary treatment of psychotic illness.
Benzodiazepines should not be used alone to treat depression or anxiety associated with depression as
suicide may occur in such patients. Patients with a history of depression and/or suicide attempts should be
kept under close supervision.
Anterograde amnesia may occur with therapeutic doses of benzodiazepines and may be associated with
inappropriate behaviour, the risk increasing with higher doses (see ADVERSE REACTIONS).
Concomitant use with opioids
Concomitant use of benzodiazepines, including DIAZEPAM, and opioids may result in profound sedation,
respiratory depression, coma and death. Because of these risks, reserve concomitant prescribing of these
drugs for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines
increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar
pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other central
nervous system (CNS) depressant drugs with opioid analgesics.
If a decision is made to prescribe DIAZEPAM concomitantly with opioids, prescribe the lowest effective
dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic,
prescribe a lower initial dose of DIAZEPAM than indicated in the absence of an opioid and titrate based on
clinical response. If an opioid analgesic is initiated in a patient already taking diazepam, prescribe a lower
initial dose of the opioid analgesic and titrate based on clinical response. Follow patients closely for signs
and symptoms of respiratory depression and sedation (see DRUG INTERACTIONS and OVERDOSE).
Advise both patients and caregivers about the risks of respiratory depression and sedation when
DIAZEPAM is used with opioids.
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Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the opioid
have been determined.
Concomitant use of alcohol and/or centrally acting depressants
The concomitant use of DIAZEPAM with alcohol and/or CNS depressants should be avoided. Such
concomitant use has the potential to increase the clinical effects of DIAZEPAM possibly including severe
sedation, that could result in coma or death, clinically relevant respiratory and/or cardiovascular depression
(see DRUG INTERACTIONS and OVERDOSE).
Patients should be advised against the concurrent use of DIAZEPAM with alcohol and/or other CNS
depressant drugs.
Medical History of Alcohol or Drug Abuse
DIAZEPAM (diazepam) should be used with extreme caution in patients with a history of alcohol or drug
abuse.
DIAZEPAM should be avoided in patients with dependence on CNS depressants including alcohol. An
exception to the latter is the management of acute withdrawal reactions.
Benzodiazepines have produced habituation, dependence and withdrawal symptoms similar to those noted
with barbiturates and alcohol. The risk of dependence increases with dose and duration, and is greater in
patients with a medical history of alcohol and drug abuse (see WARNINGS AND PRECAUTIONS,
Dependence and Tolerance).
Lactose Intolerance
Lactose is a non-medicinal ingredient in DIAZEPAM. Therefore, patients with rare hereditary problems of
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this
medicine.
Dependence/Tolerance
Dependence Liability
Use of DIAZEPAM may lead to the development of physical and psychological dependence (see
ADVERSE REACTIONS). Benzodiazepines are commonly abused in conjunction with other drugs (see
DRUG INTERACTIONS).
Tolerance
Some loss of response to the effects of benzodiazepines may develop after repeated use of DIAZEPAM
(diazepam) for prolonged time.
Withdrawal
Once physical dependence has developed, abrupt termination of treatment with DIAZEPAM will be
accompanied by withdrawal symptoms. Withdrawal symptoms may develop after a lengthy period of use at
therapeutic doses. The possibility that such effects may also occur following short-term use, especially at
high doses, or if the daily dose is reduced rapidly or abruptly discontinued, should be considered.
Symptoms of withdrawal may consist of headache, diarrhea, muscle pain, extreme anxiety, tension,
restlessness, confusional state and irritability. In severe cases, the following symptoms may occur:
derealization, depersonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to
light, noise and physical contact, hallucinations or convulsions. Since these symptoms are similar to those
for which the patient is being treated, it may appear that he/she has suffered a relapse upon discontinuation
of the drug.
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Rebound anxiety is a transient syndrome whereby the symptoms that led to treatment with DIAZEPAM
recur in an enhanced form. This may occur on withdrawal of treatment. It may be accompanied by other
reactions including mood changes, anxiety, sleep disturbances, and restlessness.
Since the risks of withdrawal symptoms and rebound anxiety are greater after abrupt discontinuation of
treatment, abrupt withdrawal of the drug should be avoided and treatment – even if only of short duration -
should be terminated by gradually reducing the daily dose (see DOSAGE AND ADMINISTRATION,
Dosing Considerations.)
Withdrawal symptoms may also develop when switching from DIAZEPAM to a benzodiazepine with a
considerably shorter elimination half-life.
Falls and fractures
There have been reports of falls and fractures among benzodiazepine users. The risk is increased in those
taking concomitant sedatives (including alcoholic beverages) and in the elderly.
Hepatic
DIAZEPAM is contraindicated in patients with severe hepatic impairment (see CONTRAINDICATIONS).
DIAZEPAM, like other benzodiazepines can precipitate or exacerbate hepatic encephalopathy.
Special caution should be exercised when administering DIAZEPAM to patients with mild to moderate
hepatic impairment. In patients with cirrhosis, a 2-to 5-fold increase in mean half-life has been reported.
Increases in half-life have also been reported in hepatic fibrosis and in both chronic and acute hepatitis. The
reduced clearance of diazepam and its active metabolite (desmethyl-diazepam) leads to their increased
accumulation during long-term dosing. This in turn is associated with increased sedation (see ACTION
AND CLINICAL PHARMACOLOGY, Special Populations and Conditions). If treatment is necessary in
patients with impaired hepatic function, it is recommended to initiate DIAZEPAM at a very low dose and
to increase the dosage only to the extent that such an increase is compatible with the degree of residual
hepatic function. If DIAZEPAM is administered for protracted periods, such patients should be monitored
closely and have periodic liver function tests.
Neurologic
Use in Epileptic Patients
Careful consideration should be given if DIAZEPAM is to be used in patients with epilepsy as the
possibility of an increase in the frequency and/or severity of grand mal seizures may require an increase in
the doses of standard anticonvulsant medication. An abrupt withdrawal of DIAZEPAM in such cases may
also be associated with the temporary increase in the frequency and/or severity of seizures.
Driving and Hazardous Activities
Since diazepam has a central nervous system depressant effect, patients should be warned against driving,
operating dangerous machinery, or engaging in other hazardous activities requiring mental alertness and
physical coordination. Sedation, amnesia, impaired concentration and impaired muscle function may
adversely affect the ability to drive or operate machinery. This effect is increased if the patient has had
alcohol.
Driving, operating machinery and other hazardous activities should be avoided altogether or at least during
the first few days of treatment. The decision on this question rests with the patient’s physician and should
be based on the patient’s response to treatment and the dosage involved. They also should be warned
against the concomitant use of DIAZEPAM with alcohol and/or other CNS depressant drugs.
Patients receiving DIAZEPAM should be advised to proceed cautiously wherever mental alertness and
physical coordination are required.
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Psychiatric
Mental and Emotional Disorders
It should be recognized that suicidal tendencies may be present in patients with emotional disorders and
that protective measures and appropriate treatment may be necessary and should be instituted without
delay.
As with other benzodiazepines, diazepam should not be used in individuals with physiological anxiety or
normal stresses of daily living, but only in the presence of disabling manifestations of an appropriate
pathological anxiety disorder.
These drugs are not effective in patients with characterological and personality disorders or those with
obsessive-compulsive disorders. Diazepam is also not recommended for management of depressive or
psychotic disorders. Benzodiazepines should not be used to treat anxiety associated with depression, as
suicide may be precipitated in these patients.
Paradoxical reactions
Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, anxiety, delusion, anger,
nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are
known to occur when using benzodiazepines, and are more likely to occur in children and the elderly.
Should this occur, the use of the drug should be discontinued.
Since excitement and other paradoxical reactions can result from the use of anxiolytic sedatives in
psychotic patients, diazepam should not be used in ambulatory patients suspected of having psychotic
tendencies.
Renal
If treatment is necessary in patients with impaired renal function, it is recommended to initiate -
DIAZEPAM at a very low dose and to increase the dosage only to the extent that such an increase is
compatible with the degree of residual renal function. If DIAZEPAM is administered for protracted
periods, such patients should be monitored closely.
Respiratory Respiratory depression may occur following administration of DIAZEPAM. This effect may be aggravated
by pre-existing airway obstruction or brain damage or if other medications which depress respiration have
been given. As a rule, this can be avoided by careful adjustment of the dose to individual requirements.
DIAZEPAM should be used with caution in patients with chronic respiratory diseases and a lower dose is
recommended due to the risk of respiratory depression.
Special Populations
Pregnant Women:
The safety of diazepam for use in pregnancy has not been established. An increased risk of congenital
malformation (e.g., congenital malformations of the heart, cleft lip and/or palate) associated with the use of
benzodiazepines during the first trimester of pregnancy has been suggested. DIAZEPAM should not be
used during pregnancy except if absolutely necessary.
Continuous administration of benzodiazepines during pregnancy may give rise to hypotension, reduced
respiratory function and hypothermia in the newborn child. Infants born to mothers who took
benzodiazepines chronically during the later stages of pregnancy may have developed physical dependence.
Withdrawal symptoms in newborn infants have occasionally been reported with this class of drug. Special
care must be taken when DIAZEPAM is used during labour and delivery, as high single doses may produce
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irregularities in the fetal heart rate and hypotonia, poor sucking, hypothermia and moderate respiratory
depression in the neonate. With newborn infants it must be remembered that the enzyme system involved in
the breakdown of the drug is not yet fully developed (especially in premature infants). If DIAZEPAM is
prescribed to a woman of childbearing potential, she should be warned to consult her physician regarding
discontinuation of DIAZEPAM if she plans to become or suspects that she is pregnant.
Nursing Women:
Diazepam passes into breast milk. Breast-feeding is therefore not recommended in patients receiving -
DIAZEPAM.
Pediatrics: Not recommended for use in children under six months. See CONTRAINDICATIONS.
Geriatrics: Elderly and debilitated patients or those with organic brain disorders have been found to be prone to central
nervous system depression following even low doses. For these patients it is recommended that the dosage
of DIAZEPAM be limited to the smallest, effective amount with incremental increases made gradually
depending on the response, to preclude development of ataxia, over sedation or other possible adverse
effects (see DOSAGE AND ADMINISTRATION).
There is an increased risk for falls and fractures among elderly and debilitated benzodiazepine users. The
risk is increased in those taking concomitant sedatives (including alcoholic beverages).
Monitoring and Laboratory Tests
If DIAZEPAM is administered for protracted periods, patients with impaired hepatic or renal function
should be monitored closely. Because of isolated reports of neutropenia and jaundice, periodic blood counts
and liver function tests are recommended during long term therapy.
ADVERSE REACTIONS
Adverse Drug Reaction Overview
The most common adverse reactions reported for diazepam are fatigue, drowsiness, muscle weakness and
ataxia; they are usually dose-related. These adverse events occur predominantly at the start of therapy and
usually disappear with prolonged administration.
Serious and Important Adverse Reactions
The more serious adverse reactions occasionally reported are leucopenia, jaundice and hypersensitivity.
Because of isolated reports of neutropenia and jaundice, periodic blood counts and liver function tests
are recommended during long term therapy.
Allergic reactions and a very few cases of anaphylaxis have been reported to occur with
benzodiazepines.
There have been reports of falls and fractures in benzodiazepine users. The risk is increased in those taking
concomitant sedatives (including alcoholic beverages) and in the elderly.
Anterograde amnesia may occur with therapeutic dosages of benzodiazepines, the risk increasing at higher
dosages. Effects of anterograde amnesia may be associated with inappropriate behaviour.
Psychiatric and paradoxical reactions: Release of hostility and other paradoxical effects such as irritability,
excitability, restlessness, agitation, aggression, delusion, anger, nightmares, hallucinations, psychoses,
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inappropriate behaviour and other adverse behavioural effects are known to occur with the use of
benzodiazepines. Should this occur, the drug should be discontinued. These effects are more likely to occur
in children and in the elderly (see WARNINGS AND PRECAUTIONS - Psychiatric and paradoxical
reactions).
Minor changes in EEG patterns have been observed in patients on diazepam therapy. These changes consist
of low to moderate voltage fast activity, 20 to 30 cycles per second and are of no known significance.
Chronic use (even at therapeutic doses) may lead to the development of physical dependence:
discontinuation of the therapy may result in withdrawal or rebound phenomena (see WARNINGS AND
PRECAUTIONS, Dependence Liability).
Abuse of benzodiazepines has been reported (see WARNINGS-General).
Post-Market Adverse Drug Reactions
Other adverse events, listed by body systems, include the following:
Cardiovascular System: Hypotension, circulatory depression, irregular heart rate, cardiac failure including
cardiac arrest.
Digestive System: Dry mouth, nausea, gastrointestinal disturbances, constipation and hypersalivation,
jaundice.
Metabolic and Nutritional Disorders: Increased transaminases, increased blood alkaline phosphatase.
Nervous System: Ataxia, tremor, vertigo, dizziness, headache, slurred speech, dysarthria, confusion,
emotional and mood disturbances, decreased alertness, depression, changes in libido, euphoria,
hypoactivity and memory impairment.
Respiratory System: Respiratory depression including respiratory failure.
Skin and Appendages: Skin rash, generalized exfoliative dermatitis.
Special Senses: Diplopia, vision blurred.
Urogenital System: Incontinence, urinary retention.
Injury, Poisoning and Procedural Complication: There have been reports of falls and fractures in
benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcoholic
beverages) and in the elderly.
DRUG INTERACTIONS
Serious Drug Interactions:
Concomitant use of DIAZEPAM and opioids (see WARNINGS AND PRECAUTIONS -
Serious Warnings and Precautions, General – Concomitant Use with opioids;
Pharmacodynamic Drug-Drug Interactions)
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Overview
The concomitant use of DIAZEPAM with opioids, alcohol and/or other CNS depressants should be
avoided as this increases the risk of profound sedation, respiratory depression, coma and death.
If DIAZEPAM is to be combined with other drugs acting on the CNS, careful consideration should be
given to the pharmacology of the agent involved because of the possible additive or potentiation of
pharmacodynamic drug effects.
Avoid concomitant us of sodium oxybate with DIAZEPAM as this may lead to increased risk of
respiratory depression
DIAZEPAM is not recommended for concomitant use with clozapine and/or for concomitant
parenteral use with olanzapine.
The metabolism of diazepam and its main metabolite, desmethyldiazepam depends on the cytochrome
P450 isozymes CYP3A4 and CYP2C19. Modulators of these enzymes may lead to changes in
diazepam disposition and effects. Stronger interactions are seen with compounds that affect more than
one of diazepam’s oxidative metabolic pathways. Inhibitors of CYP3A4 and/or CYP2C19 decrease
metabolic rate and may lead to higher than normal concentrations of diazepam and the desmethyl
metabolite and consequently to increased or prolonged sedation and anxiolytic effects. Such changes
may exacerbate diazepam’s effects in patients with increased sensitivity, e.g. due to their age, reduced
liver function or treatment with other drugs that impair oxidation. Inducers of CYP3A4 and CYP2C19
may lead to lower than expected concentrations and hence to a lack of desired efficacy.
Monitoring of serum level of phenytoin is recommended when initiating or discontinuing
DIAZEPAM.
Grapefruit juice decreases the activity of CYP3A4, which is implicated in the metabolism of diazepam,
and may contribute to increased plasma levels of the drug. This may result in excessive or prolonged
sedation. Patients should be advised to avoid grapefruit juice while taking DIAZEPAM.
Drug-Drug Interactions
Pharmacokinetic Drug-Drug Interaction (DDI)
Effect of other drugs on the pharmacokinetics of diazepam
Enzyme inhibitors
Antimycotic azole derivatives (ketoconazole, itraconazole, fluconazole and voriconazole) inhibit CYP3A4
and CYP2C19 pathways and lead to increased exposure to diazepam. In a clinical trial using a single dose
of 5 mg diazepam, fluconazole increased the AUC of diazepam 2.5-fold and prolonged elimination half-life
from 31 h to 73 h, while voriconazole increased the AUC of diazepam 2.2-fold and prolonged elimination
half-life from 31 h to 61 h. This may result in increased and prolonged sedation. Therefore, it is
recommended to avoid concomitant use of these drugs with DIAZEPAM or reduce the dose of
DIAZEPAM.
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Serotonin reuptake inhibitors (fluvoxamine and fluoxetine): Fluvoxamine inhibits CYP3A4 and CYP2C19
degradation pathways. In a clinical trial using a single dose of 10 mg diazepam, fluvoxamine increased the
AUC of diazepam 3-fold and prolonged elimination half-life from 51 h to 118 h. Exposure and time to
reach steady state of the desmethyl metabolite was also increased. Fluoxetine is a moderate inhibitor of
CYP3A4. Fluvoxamine and fluoxetine may lead to increased and prolonged sedation. For patients taking
fluvoxamine, a benzodiazepine metabolized via a non-oxidative pathway is recommended. Patients
administering fluoxetine with DIAZEPAM should be monitored closely.
Combined hormonal contraceptives appear to reduce the clearance and prolong elimination half- life of
diazepam. Monitor clinical response of DIAZEPAM in women taking concomitant oral contraception.
There is some evidence that benzodiazepines can increase the incidence of break- through bleeding in
women with hormonal contraceptives.
The proton pump inhibitors omeprazole and esomeprazole are CYP2C19 and CYP3A4 inhibitors. When
administered at a dose of 20 mg o.d., omeprazole increased the diazepam AUC by 40% and the half-life by
36%; at a dose of 40 mg o.d., omeprazole increased the diazepam AUC by 122% and the half-life by 130%.
The elimination of desmethyl-diazepam was reduced as well. The effect of omeprazole was seen in
extensive but not slow metabolizers of CYP2C19. When administered at a dose of 30 mg o.d.,
esomeprazole increased the AUC and half-life of diazepam by 80%. Therefore, it is recommended to
monitor patients administering these drugs with diazepam and reduce the dose of DIAZEPAM if necessary.
The histamine H2-receptor antagonist cimetidine, an inhibitor of multiple CYP isozymes, including
CYP3A4 and CYP2C19, reduces the clearance of diazepam and of desmethyl- diazepam by 40 to 50%.
This results in higher exposure to and a prolonged elimination half-life of diazepam and its main metabolite
after single dosing and to higher steady-state concentrations after multiple dosing of diazepam. Enhanced
sedation was also seen with co-administration of cimetidine. Therefore, when used with cimetidine, a
reduction of the dose of DIAZEPAM may be necessary.
Disulfiram inhibits the metabolism of diazepam and probably the further metabolism of diazepam’s active
metabolites. Enhanced sedative effects may result.
Antituberculosis agent therapy may change the disposition of diazepam. In presence of isoniazid diazepam
mean exposure (AUC) and half-life were increased (on average 33 to 35%) with the largest changes seen in
subjects with slow-acetylator phenotype. When used with isoniazid, monitor patients and reduce the dose
of DIAZEPAM if necessary.
The calcium channel blocker diltiazem, a substrate for the same CYP isozymes as diazepam and an
inhibitor of CYP3A4, increased AUC by approximately 25% and prolonged half-life by 34 to 43% of
diazepam in poor and extensive CYP2C19 metabolizers. In the presence of diltiazem, exposure to
desmethyl-diazepam also tended to increase. Exercise caution when using DIAZEPAM with diltiazem,
irrespective of CYP2C19 metabolizer status.
Idelalisib is a strong CYP3A4 inhibitor that increases the serum concentrations of diazepam. When used
with idelalisib, monitor patients and reduce the dose of DIAZEPAM if necessary.
The psychostimulant modafinil induces CYP3A4 and inhibits CYP2C19. This may prolong the elimination
of diazepam and cause excessive sedation. When used with modafinil, monitor patients and reduce the dose
of DIAZEPAM if necessary.
Other CYP3A or CYP2C19 inhibitors, such as clarithromycin, erythromycin, ritonavir and verapamil, may
lead to increased and prolonged sedation of DIAZEPAM.
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Enzyme inducers
Rifampicin potently induces CYP3A4 and has also a significant accelerating effect on the CYP2C19
pathway. When dosed at 600 mg or 1200 mg daily for 7 days, diazepam clearance was increased
approximately 4-fold and AUC decreased by approximately 75%. A significant reduction in exposure to all
diazepam metabolites was also observed. DIAZEPAM should not be used in combination with rifampicin.
Carbamazepine is a known inducer of CYP3A4 and accelerated elimination (increased clearance, reduced
half-life) of diazepam 3-fold while increasing concentrations of desmethyl-diazepam.
This can result in a reduced effect of DIAZEPAM.
Other pharmacokinetic interactions
Diazepam pretreatment changes the pharmacodynamics and pharmacokinetics of the anaesthetic ketamine.
Ketamine N-demethylation was inhibited leading to a prolonged half-life and prolonged ketamine-induced
sleeping time. In the presence of DIAZEPAM, a reduced ketamine concentration is required to achieve
adequate anaesthesia.
Antacids may lower the rate but will not lower the extent of diazepam absorption from the tablet; this may
lead to attenuated effects after a single dose but not influence steady-state concentrations during multiple-
dose therapy.
Prokinetic drugs increase the rate of diazepam absorption, potentially resulting in a transient increase in
sedation. Intravenous but not oral metoclopramide increases the rate of absorption of diazepam and
increases the maximum concentration achieved after oral dosing.
Effect of diazepam on the pharmacokinetics of other drugs
Phenytoin therapy was associated with higher concentrations and increased phenytoin intoxication when
combined with diazepam in some, but not all, studies. Monitoring of serum level of phenytoin is
recommended when initiating or discontinuing DIAZEPAM.
Pharmacodynamic Drug-Drug Interaction
Concomitant use with opioids, alcohol and/or other central nervous system (CNS) depressants
Due to additive CNS depressant effect, the concomitant use of DIAZEPAM with opioids, alcohol and/or
other CNS depressants (anxiolytic/sedatives, anesthetics, hypnotics and sedative antihistamines) should be
avoided. Concomitant use of DIAZEPAM with these increases the risk of profound sedation, respiratory
depression, coma and death. Patients should be advised against concurrent use. Concomitant prescribing of
DIAZEPAM and opioids should be reserved for use in patients for whom alternative treatment options are
inadequate. Limit dosages and durations of concomitant use of DIAZEPAM and opioids to the minimum
required. Follow patients closely for respiratory depression and sedation (see WARNINGS &
PRECAUTIONS - Serious Warning and Precautions box, General -Concomitant with opioids, Concomitant
use with alcohol and/or CNS depressants).
When combined with narcotic agents, DIAZEPAM may enhance euphoria, leading to an increased risk of
abuse or dependence. Diazepam increased the subjective and sedative opioid effects of methadone and
buprenorphine in a manner that may heighten abuse potential. A significantly greater deterioration in
reaction time was also observed when these drugs were combined with diazepam.
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Additive/Potentiated effects with other centrally-acting agents
If DIAZEPAM is to be combined with other drugs acting on the CNS, careful consideration should be
given to the pharmacology of the agent involved because of the possible additive or potentiation of drug
effects. Additive CNS depressant effects resulting in enhanced sedation and cardio respiratory depression
may occur when DIAZEPAM is co-administered with anticonvulsants; muscle relaxants, monoamine
oxidase inhibitor and tricyclic antidepressants;; and phenothiazine, thioxanthene and butyrophenone
antipsychotics. Sedation, respiratory depression and airway obstruction was reported with the combined use
of methotrimeprazine and diazepam.
Avoid concomitant use of sodium oxybate with DIAZEPAM as this may lead to increased risk of
respiratory depression.
There are several reports of excessive sedation, loss of consciousness, severe hypotension, or
cardiorespiratory depression sometimes resulting in death in patients under combined treatment with
clozapine or olanzapine and benzodiazepines, including DIAZEPAM. Concomitant use of DIAZEPAM and
clozapine or parenteral use of DIAZEPAM and olanzapine are not recommended.
Antagonistic interactions with centrally acting agents
Reversible loss of control of Parkinson’s disease has been seen in some patients treated with combined
levodopa and DIAZEPAM.
The xanthines theophylline and caffeine oppose the sedative and possibly anxiolytic effects of DIAZEPAM
partially through blocking of adenosine receptors.
Drug-Food Interactions
Grapefruit juice contains strong inhibitors of CYP3A4. Diazepam exposure was strongly increased (AUC
3.2-fold; Cmax 1.5-fold) and time to reach maximum concentration was delayed when diazepam was given
with grapefruit juice instead of water. This may result in excessive or prolonged sedation. Patients should
be advised to avoid grapefruit juice while taking DIAZEPAM.
Concurrent consumption of caffeine-containing foods and beverages may result in reduced sedative and
anxiolytic effects of DIAZEPAM.
Food may lower the rate but will not lower the extent of diazepam absorption from the tablet; this may lead
to attenuated effects after a single dose but not influence steady-state concentrations during multiple-dose
therapy.
Drug-Lifestyle Interactions
The concomitant use of DIAZEPAM with alcohol should be avoided. Such concomitant use has the
potential to increase the clinical effects of diazepam possibly including severe sedation, clinically relevant
respiratory and/or cardiovascular depression (see WARNINGS AND PRECAUTIONS, Concomitant use of
alcohol / CNS depressants, and OVERDOSAGE sections).
Driving, operating machinery and other hazardous activities should be avoided while taking DIAZEPAM.
Sedation, amnesia, impaired concentration and impaired muscle function may adversely affect the ability to
drive or operate machinery.
14
DOSAGE AND ADMINISTRATION
Dosing Considerations
Dosage for DIAZEPAM (diazepam) should be individualized for maximal beneficial effect. While the
usual daily dosages given below will meet the needs of most patients, there will be some who may require
higher doses.
Lower doses are recommended for elderly and debilitated patients, and patients with debilitating diseases.
In the first few days of administration a cumulative effect of drug may occur, and therefore, the dosage
should be increased only after stabilization is apparent.
The tablet can be divided into equal halves to facilitate dosing.
The duration of treatment should be as short as possible. The patient should be reassessed regularly and the
need for continued treatment evaluated, especially if the patient is symptom free. It should not exceed 2 to
3 months, including the tapering-off period. Extension beyond this period should not take place without re-
evaluation of the situation. It may be useful to inform the patient when treatment is started that it will be of
limited duration and explain precisely how the dosage will be progressively decreased. Moreover, it is
important that the patient be aware of the possibility of rebound phenomena, thereby minimizing anxiety
over such symptoms, should they occur during withdrawal. There is evidence that, in the case of short-
acting benzodiazepines, withdrawal phenomena can become manifest within the dosage interval, especially
when the dosage is high. When long-acting benzodiazepines such as diazepam are being used, it is
important to warn against changing to a short-acting benzodiazepine as withdrawal symptoms may
develop.
Recommended Dose and Dosage Adjustment
Children: Because of varied responses, initiate therapy with lowest dose and increase as required. Not for
use in children under six months. See CONTRAINDICATIONS. The initial dose should be between 1 mg
and 2.5 mg, three or four times daily initially; increase gradually as needed and tolerated.
Adults:
Symptomatic relief of anxiety and tension in psychoneurosis and anxiety reactions: Depending upon
severity of symptoms, the initial dose should be between 2 mg and 10 mg, two to four times daily.
Symptomatic relief in acute alcohol withdrawal: The initial dose should be 10 mg, three or four times
during the first 24 hours, reducing to 5 mg, three or four times daily as needed.
Adjunctively for relief of skeletal muscle spasm: The initial dose should be between 2 mg and 10 mg, three
to four times daily
Elderly and debilitated patients: Benzodiazepine pharmacologic effects appear to be greater in elderly
patients than in younger patients even at similar plasma benzodiazepine concentrations, possibly because of
age-related changes in drug–receptor interactions, post-receptor mechanisms and organ function. Therefore,
the initial dose of DIAZEPAM should be 2 mg, one or two times daily initially, increase gradually as
needed and tolerated (see WARNINGS and PRECAUTIONS - Special Populations - Geriatrics).
Hepatic impairment: DIAZEPAM is contraindicated in patients with severe hepatic impairment (see
CONTRAINDICATIONS; WARNINGS and PRECAUTIONS - Hepatic). Special caution should be
exercised when administering DIAZEPAM to patients with mild to moderate hepatic impairment. If
treatment is necessary, it is recommended to initiate DIAZEPAM at a very low dose and to increase the
15
dosage only to the extent that such an increase is compatible with the degree of residual hepatic function. If
DIAZEPAM is administered for protracted periods, such patients should be monitored closely and have
periodic liver function tests.
Renal impairment: If treatment is necessary in patients with impaired renal function, it is recommended to
initiate DIAZEPAM at a very low dose and to increase the dosage only to the extent that such an increase is
compatible with the degree of residual renal function. If DIAZEPAM is administered for protracted
periods, such patients should be monitored closely.
OVERDOSAGE
For management of a suspected drug overdose, contact your regional Poison Control Centre.
Symptoms
The main symptoms of benzodiazepine overdosage are drowsiness, over sedation, dysarthria, nystagmus,
and ataxia. When the effects of the drug overdosage begin to wear off, the patient exhibits some jitteriness
and overstimulation. Overdose of diazepam is seldom life-threatening if the drug is taken alone, but may
lead to areflexia, apnea, hypotension, cardiorespiratory depression and coma. Coma, if it occurs, usually
lasts a few hours but it may be more protracted and cyclical, particularly in elderly patients.
Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease. There
are minimum effects on respiration, pulse and blood pressure unless the overdosage is extreme.
Benzodiazepines increase the effects of other central nervous system depressants, including alcohol.
Treatment
In managing overdosage, consider the possibility of multiple drug involvement.
Monitor the patient’s vital signs and institute supportive measures as indicated by the patient’s clinical
state. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central
nervous system effects.
Further absorption should be prevented using an appropriate method e.g. treatment within
1 to 2 hours with activated charcoal. If activated charcoal is used airway protection is imperative for
drowsy patients. In case of mixed ingestion gastric lavage may be considered, however not as a routine
measure. Induction of vomiting is not generally recommended.
If CNS depression is severe consider the use of flumazenil, a benzodiazepine receptor antagonist. The
following should be kept in mind when flumazenil is used in the treatment of benzodiazepine overdosage:
Flumazenil should only be administered under closely monitored conditions. In view of the short half-
life (about 1 hour) and duration of action of flumazenil, and the possible need for repeat doses, the
patient should be closely monitored until all possible central benzodiazepine effects (e.g., resedation)
have subsided.
Particular caution is necessary when using flumazenil in cases of multiple drug overdosage, since the
toxic effects (cardiac arrhythmias and/or convulsions) of other psychotropic drugs, especially cyclic
antidepressants, may increase as the effects of benzodiazepines subside. Flumazenil is contraindicated
in patients who are showing signs of serious cyclic antidepressant overdose.
16
Warning: The benzodiazepine receptor antagonist flumazenil is not indicated in patients with epilepsy who
have been treated with benzodiazepines. Antagonism of the benzodiazepine effect in such patients may
provoke seizures.
Refer to the product monograph for flumazenil for further information on the correct use of this drug.
ACTION AND CLINICAL PHARMACOLOGY
Pharmacokinetics
Absorption: Diazepam is rapidly and completely absorbed from the gastrointestinal tract, peak plasma
concentrations appearing 30 to 90 minutes after oral ingestion.
Following daily dosing, diazepam levels reach a steady state within approximately 5 days; it takes about
twice as long before desmethyl-diazepam levels reach a steady-state. Average steady-state levels of
diazepam after once daily administration are approximately twice as high as the peak levels of the drug
after the first dose.
During treatment, the elimination half-life of diazepam may increase by 50% due to a reduction in hepatic
clearance.
Distribution: Diazepam is widely distributed into tissues despite high binding to plasma proteins (98 to 99%), mainly
albumin and to lesser extent α1-acid glycoprotein. After intravenous administration, a pronounced
distribution phase is seen in plasma concentrations with a half-life of distribution of up to 3 hours. The
volume of distribution at steady state averages between 0.88 to 1.1 L/kg when derived from plasma
concentration measurements. Both protein binding and volume of distribution of desmethyl-diazepam are
similar to those of diazepam.
Cerebrospinal fluid (CSF) levels in man following single and multiple doses approximate closely the free
drug concentration in plasma. Upon multiple dosing desmethyl-diazepam, but not diazepam, may
significantly accumulate in CSF. Diazepam has very rapid uptake into and equilibration with brain tissue,
with equilibrium concentrations in brain exceeding those in plasma.
In humans, comparable blood levels of DIAZEPAM were obtained in maternal and cord blood indicating
placental transfer of the drug.
Metabolism: Diazepam is N-demethylated by CYP3A4 and 2C19 to the active metabolite N-
desmethyldiazepam, a pathway accounting for 50 to 60% of total diazepam clearance; 3- hydroxylation
(27% of total diazepam clearance) is slow, leading to only low plasma levels of the oxidation products
temazepam and oxazepam. Oxazepam and temazepam are further conjugated to glucuronic acid.
Oxidation of diazepam is mediated by cytochrome P450 isozymes; formation of desmethyl- diazepam
mainly by CYP2C19 and CYP3A and 3-hydroxy-diazepam (temazepam) and oxazepam by CYP3A.
Because CYP2C19 is polymorphic, extensive metabolizers (EMs), and poor metabolizers (PMs) of
diazepam can be distinguished. PMs of diazepam showed significantly lower clearance (12 vs 26 mL/min)
and longer elimination half-life (88 vs 41 h) of diazepam than EMs after a single oral dose. Also, PMs had
lower clearance, higher AUC and longer elimination half-life of desmethyl-diazepam.
Excretion: The acute half-life is six to eight hours with a slower decline thereafter. Typical terminal
elimination half-life values are in the range of 24 to 48 hours for diazepam and 40 to 100 hours for the
active metabolite desmethyldiazepam. The clearance of diazepam is 20 to 40 mL/min.
17
Diazepam is almost completely metabolized before leaving the body. Oxazepam-glucuronide is the main
drug-related product in urine.
Special Populations and Conditions
Geriatric Population
The unbound fraction of diazepam correlates positively with age and was higher in elderly than in young
subjects. Age decreases the capacity of the liver for N-demethylation and 3- hydroxylation of diazepam. An
age-dependent decrease in clearance of unbound drug occurs and is responsible for the observed 2 to 4 fold
increase in elimination half-life in the elderly, with a stronger effect seen in males than females. Hence the
extent of accumulation of unbound pharmacologically active diazepam in elderly persons during multiple
dosing will be greater than in younger adults.
Hepatic impairment
Disposition of both diazepam and desmethyl-diazepam is altered in liver disease. In acute viral hepatitis,
the half-life of diazepam is increased by about 2-fold but returns slowly to normal on recovery. A more
marked (2- to 5-fold) increase in the elimination half-life is seen in patients with alcoholic cirrhosis. These
changes are primarily due to impaired hepatic metabolism; altered distribution due to changes in protein
binding may be contributory. The reduced clearance of diazepam and desmethyl-diazepam leads to their
increased accumulation during long-term dosing. This in turn is associated with increased sedation.
Renal impairment
In chronic renal failure, elimination of diazepam, as indicated by clearance of unbound drug, was similar to
that in healthy volunteers. Due to changes in plasma protein binding and tissue distribution of diazepam its
elimination half-life was shortened in renal disease from (mean ±S.E.) 92 ±23 h in control to 37 ±7 h in
renal failure subjects.
Pregnancy
Diazepam and desmethyl-diazepam readily cross the placental barrier. The fetus can also carry out N-
demethylation of diazepam. Long-term treatment leads to accumulation of both compounds in the fetus
with high levels in the fetal heart, lungs and brain.
Plasma protein binding of diazepam is decreased during pregnancy, particularly during the last trimester,
partly due to the fall in serum albumin concentration. Increased pharmacological effects may result after
acute dosing. (see WARNINGS AND PRECAUTIONS, Special Population, Pregnant Women)
Breast-feeding mothers
Diazepam and its metabolites are excreted in breast milk. Normalized for body weight, approximately 5%
of the mother’s dose reaches the baby. These amounts transferred may be large enough to show effects in
the baby. (see WARNINGS AND PRECAUTIONS, Special Population, Nursing Women).
STORAGE AND STABILITY
Preserve in tight light, resistant containers. Store at room temperature (15°C to 30C).
SPECIAL HANDLING INSTRUCTIONS
Keep this medicine out of sight and reach of children.
18
DOSAGE FORMS, COMPOSITION AND PACKAGING
DIAZEPAM 2 mg: Each white, round, flat-faced, bevelled-edge tablet, scored and engraved "APO" over
"2" on one side contains 2 mg of diazepam. Available in bottles of 100 and 1000.
DIAZEPAM 5 mg: Each yellow, round, flat-faced, bevelled-edge tablet, scored and engraved "APO" over
"5" on one side contains 5 mg of diazepam. Available in bottles of 100 and 1000.
DIAZEPAM 10 mg: Each blue, round, flat-faced, bevelled-edge tablet, scored and engraved "APO" over
"10" on one side contains 10 mg of diazepam. Available in bottles of 100 and 1000.
Composition
In addition to diazepam, each tablet contains the non-medicinal ingredients D&C yellow #10 (5 mg only),
FD&C blue #1 (10 mg only), FD&C blue #2 (10 mg only), FD&C yellow #6 (5 mg only), lactose
monohydrate, magnesium stearate, microcrystalline cellulose, starch.
19
PART II: SCIENTIFIC INFORMATION
PHARMACEUTICAL INFORMATION
Drug Substance
Proper name: Diazepam
Chemical Name: 7-Chloro-1, 3-dihydro-1-methyl-5-phenyl-2H, 4-benzodiazepin-2-one
Molecular Formula: C16H13ClN2O
Structural Formula:
Molecular Weight: 284.74 g/mol
Physicochemical Properties: Diazepam is a benzodiazepine derivative. Diazepam is a colorless, crystalline
compound, insoluble in water.
N
CCl
CH3
CO
CH2
N
20
DETAILED PHARMACOLOGY
In laboratory animals, diazepam was shown to possess sedative, muscle relaxant and anticonvulsant
properties.
Diazepam has a taming effect in fighting mice and vicious monkeys and a calming effect on the irritability
of rats with septal lesions. Diazepam causes sedation in cats at a dose which depresses the EEG activity of
the cortex, hippocampus, amygdala and septum.
Diazepam is active as a muscle relaxant in the inclined screen test in mice, in blocking decerebrate rigidity
in cats and in blocking the spinal reflex in cats anaesthetized with chloralose.
Diazepam has demonstrated anticonvulsant activity in antistrychnine, anti-metrazol, anti-maximal
electroshock and, to a lesser degree, anti-minimal electroshock tests in mice.
Diazepam has shown minimal or no effect in anti-Parkinsonism activity in monkeys, anti-emetic activity in
dogs, cardiovascular effects in dogs and endocrine effects in rats and rabbits.
TOXICOLOGY
Acute toxicology studies in mice have revealed the following results:
1) 1) oral LD50 720 mg/kg
2) 2) i.v. LD50 >100 mg/kg
In a forty-two week chronic toxicity study in rats diazepam was administered in doses up to and including
240 mg/kg/day; no abnormalities were observed on normal growth, food consumption, blood counts, gross
and microscopic findings.
Reproduction studies in rats have been performed with diazepam in oral doses of 1, 10, 80, and 100
mg/kg/day. At the lower dose levels the survival of offspring was within normal limits. Further studies in
rats at oral doses up to and including 80 mg/kg/day did not confirm a teratological effect on the offspring.
At the 100 mg/kg dose level there was a decrease in the number of pregnancies and surviving offspring and
several neonates showed skeletal or other defects.
The carcinogenic potential of oral diazepam has been studied in several rodent species. An increase in the
incidence of hepatocellular tumours occurred in male mice. No significant increase in the incidence of
tumours was observed in female mice, rats, hamsters or gerbils.
A number of studies have provided weak evidence of a mutagenic potential at high concentrations which
are, however, far above therapeutic doses in humans.
Diazepam was found to be teratogenic in mice at dose levels of 45 to 50 mg/kg, 100 mg/kg, and 140
mg/kg/day as well as in hamsters at 280 mg/kg. In contrast, this drug was shown to be non teratogenic at 80
and 300 mg/kg/day in rats and at 20 and 50 mg/kg/day in rabbits.
21
REFERENCES
1. Baughman VL, et al. Effectiveness of triazolam, diazepam and placebo as preanesthetic medications.
Anesthesiology 1989; 71:196-200.
2. CPMP Guidelines. Summary of product characteristics (part 1 B) for benzodiazepines as anxiolytics.
Committee for Proprietary Medicinal Products (CPMP) III/3653/91-EN, Revision 1FINAL,
Corrigendum.
3. Goldberg HL, Finnerty RJ. The comparative efficacy of buspirone and diazepam in the treatment of
anxiety. American Journal of Psychiatry 1979;136: 1184-1187.
4. Griffiths AP, Sylvester PE. Clinical trial of diazepam in adult cerebral palsy. Ann Phys Med 1964;
Suppl: 25-29.
5. Lorish TR, Thorsteinsson G, Howard FM. Stiff-man syndrome updated. Mayo Clinic Proceedings
1989;64:629-636.
6. Marsh HO. Diazepam in incapacitated cerebral-palsied children. JAMA 1965;9:797-800.
7. Rickels K, et al. Buspirone and diazepam in anxiety: a controlled study. Journal of Clinical Psychiatry
1982;43:81-86.
8. Product Monograph - VALIUM® 5 mg Tablets. Hoffmann-La Roche Ltd. Date of Revision April 17,
2018 (Control Number 212691)
IMPORTANT: PLEASE READ
22
PART III: CONSUMER INFORMATION
DIAZEPAM
Diazepam Tablets, USP
2 mg, 5 mg, and 10 mg
This leaflet is a part of the "Product Monograph"
published for DIAZEPAM and is designed
specifically for Consumers.
Please read this information before you start to
take your medicine. Keep this leaflet until you have
finished all your tablets, as you may need to read it
again. If you are helping someone else to take
DIAZEPAM, read this leaflet before you give the
first tablet.
This leaflet is a summary and will not tell you
everything about DIAZEPAM. Contact your doctor
or pharmacist if you have any questions about the
drug.
ABOUT THIS MEDICATION
What the medication is used for:
DIAZEPAM is used for the short-term relief of
severe anxiety.
DIAZEPAM is used to reduce muscle spasms
caused by medical conditions such as local trauma
or by disorders such as cerebral palsy, paraplegia
and “stiff man syndrome”.
DIAZEPAM can also be used to treat trembling,
confusional states or anxiety associated with
alcohol withdrawal
What it does:
DIAZEPAM contains the active ingredient diazepam,
which belongs to a group of medicines known as
benzodiazepines. DIAZEPAM has sedative properties
which help in the treatment of anxiety.
When it should not be used:
If you are allergic to the group of medicines
known as benzodiazepines (examples:
clonazepam, chlordiazepoxide, bromazepam, or
flurazepam).
If you are allergic to the medicinal ingredient
(diazepam)
If you are allergic to any of the other ingredients it
contains (see ‘What the non-medicinal
ingredients are’).
If you suffer from lung disease or have sleep
apnea
If you have a liver condition
If you have glaucoma
If you have myasthenia gravis
In children under 6 months.
What the medicinal ingredient is:
Diazepam
What the non-medicinal ingredients are:
The non-medicinal ingredients in DIAZEPAM are:
D&C yellow #10 (5 mg only), FD&C blue #1 (10 mg
only), FD&C blue #2 (10 mg only), FD&C yellow #6
(5 mg only), lactose monohydrate, magnesium
stearate, microcrystalline cellulose, starch.
What dosage forms it comes in:
DIAZEPAM is available as:
2 mg, 5 mg & 10 mg tablets.
WARNINGS AND PRECAUTIONS
DIAZEPAM may affect your ability to be alert.
Driving, operating machinery and other hazardous
activities should therefore be avoided altogether or
at least during the first few days of treatment. This
effect of DIAZEPAM may be made worse if you
take alcoholic drinks. If your doctor has increased
your dose or if you have changed the timings of
when you take your medication this may also
modify your reactions.
You must not consume alcohol or other drugs that
affect the central nervous system while taking
DIAZEPAM (see INTERACTIONS WITH THIS
MEDICATION below).
Always contact your doctor before stopping or
reducing your dosage of DIAZEPAM, as suddenly
stopping treatment or a large decrease in dose can
cause withdrawal symptoms.
Benzodiazepines such as DIAZEPAM have
produced dependence (addiction) and withdrawal
symptoms can occur when treatment is stopped
suddenly or switched to another benzodiazepine.
The risk of dependence (addiction) increases with
higher doses and longer duration of treatment.
Symptoms of withdrawal may include shaking,
sweating, sleep disturbances, agitation/restlessness,
headache, muscle pain, anxiety, confusion, and
irritability. In severe cases of withdrawal,
symptoms may include numbness and tingling of
the extremities, hallucinations (see or hear things
Serious Warnings and Precautions
Taking DIAZEPAM with opioid medicines can
cause severe drowsiness, decreased awareness,
breathing problems, coma and death.
IMPORTANT: PLEASE READ
23
that are not there), increased sensitivity to light,
noise and physical contact, and seizures.
There have been reports of falls and fractures in
people who take benzodiazepines such as
DIAZEPAM. The risk is increased in those also
taking other sedatives (including alcoholic
beverages) and in the elderly.
Memory loss may occur when DIAZEPAM is used
at therapeutic doses.
If you develop any unusual or disturbing thoughts
or behaviour while using DIAZEPAM, discuss the
matter immediately with your doctor.
Do not take this medicine if you are pregnant, or
might become pregnant, unless advised by your
doctor. Contact your doctor if you think you may
be pregnant, or are intending to become pregnant.
DIAZEPAM passes into breast milk. Therefore, if
you are breast feeding, this medicine should be
avoided. Your doctor will discuss this with you.
BEFORE you use DIAZEPAM talk to your doctor
or pharmacist if you:
Have a lung, liver or kidney condition.
Have glaucoma.
Are taking or plan on taking ANY other drugs
(including herbal preparations, drugs you
purchase without prescriptions, and those not
prescribed by your doctor).
Regularly drink alcohol or use recreational drugs
or have a history of dependence /addiction to
alcohol or drugs.
Have a history of depression and/or suicide
attempts.
Have the rare hereditary problems of galactose
intolerance.
Are pregnant or plan on becoming pregnant
INTERACTIONS WITH THIS MEDICATION
Tell your doctor if you are taking any other
medicines including any that you have bought from
a pharmacy, supermarket or health food store
without a prescription.
Some medicines may interact with DIAZEPAM.
These medicines include:
medicines to control seizures (flumazenil,
carbamazepine, phenytoin)
narcotics and narcotic pain relievers (opioids)
(see Serious Warnings and Precautions box)
muscle relaxants
sleeping medication or hypnotics (ketamine)
antihistamines or allergy medications.
medications to control fungus infections
(ketoconazole, itraconazole, fluconazole and
voriconazole)
medications to control viral infections (ritonavir)
birth control medications
medications to help digestion, prevent heartburn
(such as antacids omeprazole or esomeprazole) or
treat ulcers (cimetidine)
medications to treat cancer of the blood
(idelalisib)
medications to treat addiction to drugs
(methadone, buprenorphine) or alcohol
(disulfiram)
antibiotic medications to treat bacterial infections,
including tuberculosis (clarithromycin,
erythromycin, isoniazid, rifampicin)
medications used to treat high blood pressure
(diltiazem, verapamil)
medications used to treat narcolepsy and shift
work disorder (modafinil, sodium oxybate)
medicines to treat your anxiety or mood, such as
monoamine oxidase inhibitors, tricyclic
antidepressants, serotonin specific reuptake
inhibitors (fluvoxamine, fluoxetine)
medications to treat psychosis
(methotrimeprazine, clozapine, olanzapine)
medications to treat Parkinson’s disease
(levodopa)
medications to help you stay awake (theophylline
and caffeine)
These medicines may be affected by DIAZEPAM or
may affect how well DIAZEPAM works. Your doctor
or pharmacist can tell you what to do if you are taking
any of these medicines.
You must not consume alcohol while taking
DIAZEPAM as its effects may worsen side effects that
some patients experience with DIAZEPAM.
Do not drink grapefruit juice during the time that you
are taking DIAZEPAM.
If you have not told your doctor about any of the
above, tell him/her before you start taking
DIAZEPAM.
PROPER USE OF THIS MEDICATION
Usual dose:
Always take the tablets exactly as your doctor tells you
to. Your doctor will prescribe a suitable dose for you.
The dose your doctor prescribes will depend on the
nature of your illness, your reaction to the medicine,
your age and body weight. The table below shows the
IMPORTANT: PLEASE READ
24
different doses that your doctor may prescribe
according to your age. Your doctor will start you on an
initial low dose and gradually increase it until the
desired effect is achieved.
Usual Daily Dose
Adults
Relief of Severe
anxiety and tension
Depending upon severity of
symptoms – 2 mg to 10 mg, two to
four times daily.
Relief of Acute
Alcohol Withdrawal
10 mg, three or four times during
the first 24 hours, reducing to 5
mg, three or four times daily as
needed.
Relief of severe
muscle spasm
2 mg to 10 mg, three to four times
daily.
Elderly 2 mg, one or two times daily
initially, increase gradually as
needed and tolerated
Children (7 months
and older)
1 mg to 2.5 mg, three or four times
daily initially; increase gradually
as needed and tolerated.
The total daily dose should be taken as advised by
your doctor.
Do not change the prescribed dose yourself. If you
think the effect of your medicine is too weak or too
strong, talk to your doctor.
Your doctor will advise you when to stop taking the
medicine. Your doctor will slowly decrease the dosage
as sudden discontinuation of treatment can cause the
appearance of withdrawal symptoms.
Overdose:
In case of drug overdose, contact a health care
practitioner, hospital emergency department or
regional Poison Control Centre immediately, even if
there are no symptoms.
SIDE EFFECTS AND WHAT TO DO ABOUT THEM
Like all medications DIAZEPAM can cause some side
effects. For most patients these side effects are likely
to be minor and temporary as your body adjusts to the
medicine. However, some may be serious. Consult
your doctor or pharmacist as soon as you can if you do
not feel well while taking DIAZEPAM.
The most common side effects are:
Feeling drowsy or tired, especially at the start of
treatment.
Some muscle weakness and dizziness.
Less common possible side effects are:
Changes in your skin colour, nausea, headache,
blurred vision, tremors, hypotension (low blood
pressure), urinary incontinence, and constipation.
Memory loss may occur in some patients using
DIAZEPAM.
In rare cases changes in your blood and liver may
occur and your doctor will monitor for these.
Falls and fractures: The risk is increased in those
also taking other sedatives (including alcoholic
beverages) and in the elderly.
Withdrawal-related side effects:
With long-term DIAZEPAM treatment
development of physical and psychological
dependence may occur. If treatment is stopped
suddenly symptoms of withdrawal may occur,
including: headache, muscle pain, extreme
anxiety, tension, restlessness, confusion and
irritability. In severe cases of withdrawal,
symptoms may include numbness and tingling of
the extremities, hallucinations, increased
sensitivity to light, noise and physical contact, and
epileptic seizures.
SERIOUS SIDE EFFECTS, HOW OFTEN THEY
HAPPEN AND WHAT TO DO ABOUT THEM
Symptom / effect Talk with
your doctor or
pharmacist Stop taking
drug and
seek medical
help
Only
if
severe
In all
cases
Rare Unusual
behavioural
problems
(aggression, rage,
sudden anxiety or
excitation;
restlessness,
agitation,
irritability;
hallucinations
(see or hear things
that are not there)
or delusions;
severe sleep
disturbances,
nightmares,
inappropriate
behaviour
Allergic reactions
(red skin, hives,
itching, swelling
Immediately
IMPORTANT: PLEASE READ
25
of the lips, face,
tongue, throat,
trouble breathing,
wheezing,
shortness of
breath, skin
rashes, blisters of
the skin, sores or
pain in the mouth
or eyes)
Depression.
Symptoms may
include: difficulty
sleeping, changes
in weight,
feelings of
worthlessness,
guilt, regret,
helplessness or
hopelessness,
withdrawal from
social situations,
family gatherings
and activities with
friends, reduced
libido (sex drive),
and thoughts of
death or suicide.
This is not a complete list of side-effects. If you are
concerned about these or any other unwanted side-
effects, talk to your doctor or pharmacist.
HOW TO STORE IT
Keep DIAZEPAM in tight, light resistant
containers. Store at room temperature (15°C to
30°C).
Keep this medicine out of the reach and sight of
children.
Reporting Side Effects
You can report any suspected side effects associated
with the use of health products to Health Canada by:
Visiting the Web page on Adverse Reaction
Reporting (https://www.canada.ca/en/health-
canada/services/drugs-health-products/medeffect-
canada/adverse-reaction-reporting.html) for
information on how to report online, by mail or by
fax; or
Calling toll-free at 1-866-234-2345.
NOTE: Contact your health professional if you need
information about how to manage your side effects. The
Canada Vigilance Program does not provide medical
advice.
MORE INFORMATION
If you want more information about DIAZEPAM:
Talk to your healthcare professional
Find the full product monograph that is prepared
for healthcare professionals and includes this
consumer information by visiting the Health
Canada website (https://www.canada.ca/en/health-
canada.html); the manufacturer’s website
https://www.aapharma.ca/en/, or by calling 1-877-
998-9097.
This leaflet was prepared by AA Pharma Inc.
Last revised: January 07, 2019
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